目的:Astatine(211At)是一种有前途的α发射体,可替代碘(131I)。我们正在与制药和医疗器械机构协商,准备针对分化型甲状腺癌的靶向α治疗的首次人体(FIH)临床试验。这里,我们在可靠性标准下进行了延长的单剂量毒性检查,作为[211At]NaAt的临床前安全性评估,以确定FIH剂量。
方法:[211At]将NaAt溶液注射到正常的6周龄小鼠中(雄性(n=50)和雌性(n=50),体重:男33.2±1.7克,女性27.3±1.5g),然后分为四组:5MBq/kg(n=20),20MBq/kg(n=20),50MBq/kg(n=30),盐水对照(n=30)。对小鼠随访5天(急性毒性的主要评价点:n=80)或14天(n=20:恢复的评价点)以监测一般状况和体重变化。在观察期结束时,尸检,验血,器官重量测量,并进行组织病理学检查。对于体重,验血,和器官重量,进行统计学分析以比较对照组和注射组之间的数据.
结果:在小鼠的一般情况下没有观察到异常发现。在50MBq/kg组中,与对照组相比,雄性(第3天和第5天)的体重显着下降。然而,超过自发性病变范围的尸检没有显著差异.在血液测试中,男性(50MBq/kg)和女性(50MBq/kg)在第5天显示白细胞和血小板计数减少,在第14天恢复。在睾丸里,在第14天观察到体重明显下降(50MBq/kg),在所有小鼠中都观察到多核巨细胞,表明与[211At]NaAt的管理有关的重大变化。
结论:在[211At]NaAt的扩展单剂量毒性研究中,高剂量给药导致体重减轻,短暂性骨髓抑制,和睾丸的病理变化,这需要在FIH临床试验中考虑。
OBJECTIVE: Astatine (211At) is a promising alpha emitter as an alternative to iodine (131I). We are preparing the first-in-human (FIH) clinical
trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [211At]NaAt to determine the FIH dose.
METHODS: [211At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups.
RESULTS: No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [211At]NaAt.
CONCLUSIONS: In the extended single-dose toxicity
study of [211At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical
trial.